PROJECT SUMMARY This proposal seeks to define the mechanisms that contribute to sex-specific differences in anthracycline cardiotoxicity. The project will be led by Dr. Aarti Asnani, a physician-investigator at Beth Israel Deaconess Medical Center (BIDMC) and an Instructor at Harvard Medical School (HMS). Based on her chemistry background and clinical expertise, Dr. Asnani is uniquely well-positioned to characterize the biochemical pathways that contribute to anthracycline cardiotoxicity in order to identify new cardioprotective strategies. Dr. Asnani was recruited to BIDMC in 2017, where she currently serves as the Associate Director of the Cardio-Oncology Program. For this project, she will collaborate with Dr. Robert Gerszten, Chief of Cardiovascular Medicine at BIDMC and Professor of Medicine at Harvard Medical School. Dr. Gerszten has extensive experience in mass spectrometry-based metabolomic profiling to uncover new mechanisms of cardiometabolic disease. He will serve as an advisor for Dr. Asnani?s project and supervise the mass spectrometry experiments outlined in her proposal. For statistical analyses of data collected from the BIDMC retrospective cardiotoxicity patient registry, Dr. Asnani will work specifically with Michelle Keyes, PhD, a senior statistician in Dr. Gerszten?s group. Dr. Keyes received her PhD under the mentorship of Dr. Martin Laron, who is Director of Statistics for the Framingham Heart Study and Professor of Medicine at Boston University Medical Center. Dr. Pier Paolo Pandolfi will also serve as a collaborator and advisor for Dr. Asnani?s project, given his extensive experience in cancer biology and the use of mouse models to develop antitumor therapies. He is the Director of the BIDMC Cancer Center and Cancer Research Institute, Chief of the Division of Genetics in the BIDMC Department of Medicine, and a Professor of Medicine and Pathology at Harvard Medical School. At BIDMC, Dr. Asnani benefits from strong institutional support and a rich research environment. She has access to a broad range of core facilities and equipment, scientific expertise, and opportunities for collaboration that extend across BIDMC, the Longwood Medical Area, and HMS. In this proposal, Dr. Asnani has outlined a series of approaches to elucidate the role of estrogen metabolism as a potential mediator of sexual dimorphism in anthracycline cardiotoxicity. Using a mouse model of chronic doxorubicin cardiomyopathy, she will determine how modulation of CYP1-mediated estradiol metabolism confers cardioprotection in a sex-specific manner. She will also investigate how sex-specific differences in mitochondrial biogenesis contribute to the development of cardiotoxicity in this model. Finally, she will assess the role of estrogen metabolism in the BIDMC retrospective cardiotoxicity registry, which includes 1954 patients treated with anthracyclines for non-estrogen-dependent tumors. If successful, this line of investigation may enable the use of higher and more effective doses of anthracyclines in patients at low risk of cardiotoxicity and ultimately facilitate the development of new cardioprotective therapies.